Ambrose Anastasia, McNiven Vanda, Wilson Diane, Tempes Aleksandra, Underwood Mary, Chau Vann, Schulze Andreas, Wyszynska Agnieszka, Desch Karl, Malik Anna R, Mercimek-Andrews Saadet
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, Hamilton, Ontario, Canada.
Neurol Genet. 2025 Jan 13;11(1):e200232. doi: 10.1212/NXG.0000000000200232. eCollection 2025 Feb.
Neonatal encephalopathy (NE) is characterized by an abnormal level of consciousness with or without seizures in the neonatal period. It affects 1-6/1,000 live term newborns. We applied genome sequencing (GS) in term newborns with NE to investigate the underlying genetic causes.
We enrolled term newborns according to inclusion/exclusion criteria during their Neonatal Intensive Care admission. We performed GS trio and applied bioinformatic tools. We developed pipelines for manual filters. We applied in silico prediction tools, protein 3D modeling, and functional characterization to assess the pathogenicity of variants.
Seventeen newborns fulfilled inclusion criteria. We identified 12 variants in 10 genes. We classified 4 variants in , , , and (previously established disease genes) as pathogenic/likely pathogenic; 7 variants in (previously established disease gene), , , , , and (5 candidate genes) as variants of uncertain significance (VUS); and one variant in as likely benign. The and copy number variants (CNVs) resulted in structural changes in protein 3D models. The functional characterization of VUS revealed disruption of SorCS2 dimer formation and confirmed its pathogenicity. The functional characterization of variants updated their characterization from VUS/likely benign to benign. The VUS resulted in a shift in 3D protein structure. We were not able to perform protein 3D modeling and functional characterization of two VUS. We are not certain whether and variants may be causative of NE in our study.
The diagnostic rate of research GS was 41% in our prospective study. We broaden the phenotypic spectrum of -associated Hogue-Janssens syndrome 1, -associated nemaline myopathy 7, and -associated oculo-facio-cardio-dental syndrome to include NE and/or neonatal seizures. We identified 3 candidate genes () that may cause NE. We believe that protein 3D modeling is an important tool to assess the pathogenicity of CNVs and may advance the discoveries of novel genetic diseases. However, functional characterization of missense variants is essential for discoveries of novel genetic diseases. It seems that GS can help identify more candidate genes compared with ES.
新生儿脑病（NE）的特征是新生儿期意识水平异常，伴或不伴有惊厥。其发病率为每1000例足月活产新生儿中有1 - 6例。我们对足月NE新生儿应用基因组测序（GS）来探究潜在的遗传病因。
我们在新生儿重症监护病房收治期间，根据纳入/排除标准纳入足月新生儿。我们进行了GS三联体检测并应用生物信息学工具。我们开发了手动筛选流程。我们应用计算机预测工具、蛋白质三维建模和功能特征分析来评估变异的致病性。
17例新生儿符合纳入标准。我们在10个基因中鉴定出12个变异。我们将位于 、 、 及 （先前已确定的疾病基因）中的4个变异分类为致病/可能致病；位于 （先前已确定的疾病基因）、 、 、 、 及 （5个候选基因）中的7个变异分类为意义未明的变异（VUS）；位于 中的1个变异分类为可能良性。 和 的拷贝数变异（CNV）导致蛋白质三维模型发生结构变化。对1个VUS的功能特征分析揭示了SorCS2二聚体形成的破坏并证实了其致病性。对2个变异的功能特征分析将其特征从VUS/可能良性更新为良性。1个VUS导致三维蛋白质结构发生改变。我们无法对2个VUS进行蛋白质三维建模和功能特征分析。在我们的研究中，我们不确定 和 的变异是否可能是NE的病因。
在我们的前瞻性研究中，研究性GS的诊断率为41%。我们拓宽了与 相关的霍格 - 扬森综合征1、与 相关的杆状体肌病7和与 相关的眼 - 面 - 心 - 牙综合征的表型谱，使其包括NE和/或新生儿惊厥。我们鉴定出3个可能导致NE的候选基因（ ）。我们认为蛋白质三维建模是评估CNV致病性的重要工具，可能会推动新型遗传疾病的发现。然而，错义变异的功能特征分析对于新型遗传疾病的发现至关重要。与外显子组测序（ES）相比，GS似乎有助于鉴定更多的候选基因。
